'Para-retinal' Vector Administration into the Deep Vitreous Enhances Retinal Transgene Expression
| Autor: | Joshua T. Bartoe, Ryan F. Boyd, Lisa L. Wei, Henry E. Wiley, Paul A. Sieving, Yong Zeng, Dario Marangoni |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty genetic structures lcsh:QH426-470 Transgene Neurodegenerative Eye Article intravitreal delivery 03 medical and health sciences Transduction (genetics) chemistry.chemical_compound 0302 clinical medicine Ophthalmology Injection site Genetics Medicine lcsh:QH573-671 Molecular Biology Eye Disease and Disorders of Vision Retina business.industry ocular delivery lcsh:Cytology Neurosciences Retinal Intravitreal administration Gene Therapy eye diseases AAV vector lcsh:Genetics 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Molecular Medicine sense organs Ranibizumab AAV8 business Large size medicine.drug |
| Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 18, Iss, Pp 422-427 (2020) Molecular Therapy. Methods & Clinical Development |
| ISSN: | 2329-0501 |
| Popis: | Intravitreal administration for human adeno-associated vector (AAV) delivery is easier and less traumatic to ocular tissues than subretinal injection, but it gives limited retinal transduction. AAV vectors are large (about 4,000 kDa) compared with most intraocular drugs, such as ranibizumab (48 kDa), and the large size impedes diffusion to reach the retina from the usual injection site in the anterior/mid-vitreous. Intuitively, a preferred placement for the vector would be deep in the vitreous near the retina, which we term “para-retinal” delivery. We explored the consequences of para-retinal intravitreal delivery in the rabbit eye and in non-human primate (NHP) eye. 1 h after para-retinal administration in the rabbit eye, the vector concentration near the retina remained four times greater than in the anterior vitreous, indicating limited vector diffusion through the gelatinous vitreous matrix. In NHP, para-retinal placement showed greater transduction in the fovea than vector applied in the mid-vitreous. More efficient retinal delivery translates to using lower vector doses, with reduced risk of ocular inflammatory exposure. These results indicate that para-retinal delivery yields more effective vector concentration near the retina, thereby increasing the potential for better retinal transduction in human clinical application. Graphical Abstract The authors explored an alternate approach to standard intravitreal administration called “para-retinal” delivery where AAV vectors were placed deep into the vitreous near the retina surface. This modification increased vector concentration in the posterior vitreous in rabbit eyes, minimized vector losses, and enhanced foveal transgene expression in NHP eyes. |
| Databáze: | OpenAIRE |
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